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Natural Killer NK and CAR-NK Cell Expansion Method using Membrane Bound-IL-21-Modified B Cell Line

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Sarcoma IL-12 overexpression facilitates NK cell immunomodulation.

Mary Jo Rademacher¹, Anahi Cruz¹, Mary Faber¹

¹Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.

Scientific Reports

|April 16, 2021

Summary

Lentiviral transduction of sarcoma cells to produce Interleukin-12 (IL-12) shows promise for cancer immunotherapy. This approach localized IL-12 delivery, enhancing immune responses and restricting tumor growth in preclinical models.

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Area of Science:

Oncology
Immunotherapy
Gene Therapy

Background:

Interleukin-12 (IL-12) is a potent cytokine for cancer immunotherapy.
Systemic IL-12 administration causes significant toxicities.
Localized delivery strategies are needed to harness IL-12's therapeutic potential.

Purpose of the Study:

To engineer human sarcoma cells to produce IL-12 via lentiviral transduction for localized immunotherapy.
To evaluate the in vitro and in vivo efficacy of IL-12-expressing sarcoma in preclinical models.

Main Methods:

Human sarcoma cell lines and primary samples were transduced with lentivirus to express human IL-12 (hu-IL-12).
IL-12 expressing sarcomas were assessed in vitro for immune cell activation and tumor cell growth inhibition.
In vivo studies utilized humanized NSG and NSG.Tg(Hu-IL-15) murine models with orthotopic xenografts.

Main Results:

Lentiviral transduction successfully generated high-level hu-IL-12 expression in various human sarcoma types.
In vitro, hu-IL-12 induced NK cell-mediated interferon-γ (IFN-γ) release and inhibited tumor spheroid growth.
In vivo, LV/hu-IL-12 transduced sarcomas elicited an IFN-γ response in humanized mice and restricted tumor growth.

Conclusions:

Lentiviral transduction of sarcoma for IL-12 production is a viable strategy for localized immunotherapy.
The humanized NSG.Tg(Hu-IL-15) model with mature human NK cells is suitable for evaluating anti-sarcoma immune responses and toxicities.
Autologous tumor transduction with IL-12 warrants further investigation for sarcoma treatment.